For a living body, the inside of the intestinal tract is equivalent to the outside of the body and is always exposed to a very wide variety and large number of intestinal indigenous bacteria, viruses, and antigens derived from, for example, food. These intestinal indigenous bacteria form gut microbiota (hereinafter “gut microbiota” may be referred to as “intestinal bacterial flora”).
It has been clarified that gut microbiota performs various functions in a living body via mucosal surfaces constructed with intestinal epithelial cells and other cells. It has also been found that when intestinal bacteria are not present, the intestinal immune system cannot normally develop (Non-patent Literature (NPL) 1 to 3).
If gut microbiota undergoes a change, and the symbiotic balance between the host and intestinal bacteria is disrupted, the homeostasis of the intestinal immune system is disrupted due to the intestinal immune system being overly stimulated. As a result, many diseases, such as inflammatory bowel disease, colorectal cancer, asthma, allergies, and obesity, may be induced with the disruption of the homeostasis. In view of this, the intestinal immune system is known to play an important role not only in eliminating pathogens, etc., but also in maintaining homeostasis of the whole immune system (Non-patent Literature (NPL) 4 to 7).
The surface of mucosal tissue in the gastrointestinal tract is a route by which antigens, such as indigenous bacteria, pathogenic microorganisms, and allergens, invade a living body. The surface of mucosal tissue is continuously attacked as the site where these many pathogenic microorganisms from the external environment invade, and is exposed to various antigens. The system for recognizing and/or responding to foreign antigens, including these pathogenic microorganisms, is called the mucosal immune system. Many cells that are responsible for mucosal immune system are present immediately below the surface of mucosal tissue in the gastrointestinal tract. These cells form a dynamic immune organization by which an immune response occurs against pathogenic microorganisms, food antigens, allergens, exogenous foreign antigens, and the like.
The mucosal immune system constructs a unique immune system that is based on an IgA antibody derived from an intestine against foreign exogenous antigens taken up through the mucosal surface constructed with intestinal epithelial cells. The intestine-derived IgA antibody is produced not only within specific tissues that are sites of immune response, such as Peyer's patches, mesenteric lymph nodes, and isolated lymphoid follicles, in a T-cell-dependent manner, but also produced in a large amount by antibody-producing cells disseminated among the intestinal lamina propria (Non-patent Literature (NPL) 8 and 9).
One of the functions of the intestine-derived IgA antibody is to eliminate pathogens. The intestine-derived IgA antibody secreted into the lumen binds to pathogens and their toxins in the intestinal lumen and neutralizes them. Alternatively, the intestine-derived IgA antibody binds to pathogens, toxins, etc., that invade intestinal epithelial cells, lamina propria, and the like, and neutralizes them while eliminating them as the intestine-derived IgA antibody itself is secreted into the lumen. A feature of the function of intestine-derived IgA antibody is that they do not cause inflammatory reactions, unlike reactions of the systemic immune system in which general antibodies are involved (Non-patent Literature (NPL) 10 to 12).
Another function of intestine-derived IgA antibody is to maintain the symbiotic relationship between intestinal indigenous bacteria and their hosts. An intestine-derived IgA antibody recognizes and binds to not only pathogens but also indigenous bacteria to prevent excessive entry of indigenous bacteria into the mucous membrane. In addition, it is believed that indigenous bacteria are not eliminated by intestine-derived IgA, and that intestine-derived IgA antibodies binding to indigenous bacteria are localized in the mucin layer on epithelial cells and form a biological film with the indigenous bacteria, in which the biological film prevents pathogens from contacting or invading the epithelial cells (Non-patent Literature (NPL) 13 and 14).
In relation to these intestinal mucosal immune systems, somatic hypermutation and class switching of antibody are known to play an important role to construct, in particular, the humoral immune system. Somatic hypermutation is a mechanism that is provided in vivo so as to diversify the immunoglobulin gene of antibody-producing B cells and produce high-affinity antibodies. Antibody class switching is a phenomenon in which the structure of the H-chain constant region is changed while the variable region of the antibody is maintained. In other words, antibody class switching is a phenomenon in which the class of immunoglobulin generated from a selected cell producing an IgM antibody is changed to different classes of immunoglobulins, such as IgG, IgE, and IgA, with the same variable region as the IgM. Due to a combination of somatic hypermutation and class switch recombination of the antibody, a variety of antibodies with various antigen-binding sites is produced, and antibodies of each class with respect to each antigen-binding site are produced. As a result, it is possible to appropriately regulate the immune functions in the body.
Both somatic hypermutation and class switching are known to require an activation-induced cytidine deaminase (AID) protein. The N-terminal domain of the AID protein is known to be involved in somatic hypermutation, while C-terminal domain of AID protein is known to be involved in class switching (Non-patent Literature (NPL) 15 and 16). In somatic hypermutation, AID is highly likely to cause DNA cleavage in an antibody gene, and the DNA cleavage triggers the introduction of mutation in an antibody gene (Non-patent Literature (NPL) 17).
In mice expressing AID-G23S (AID G23S mouse), which carries one amino acid substitution (glycine to serine) at position 23 of the AID protein, class switching occurs, and antibodies of each class are sufficiently produced. However, somatic hypermutation does not occur, and antigen-binding ability of the antibodies is reduced in an AID G23S mouse (Non-patent literature (NPL) 18).
Inflammatory bowel disease is difficult to cure and is thus specified as an intractable disease. This disease is an example of diseases caused by disruption of the balance between the host immune system and intestinal bacteria, i.e., alternation of intestinal bacterial growth and/or pathological changes of intestinal bacterial growth in gut microbiota (“alternation of intestinal bacterial growth and/or pathological changes of intestinal bacterial growth in gut microbiota” may be refer to as “dysbiosis”). In a clinical setting, this disease is treated by systemic administration of an immunosuppressant agent, such as a steroid and an anti-TNF antibody. However, these drugs require long-term administration, and a significant problem of side effects arises from these drugs. Therefore, it is desired that a medicinal drug that has reduced side effects and that is effective in treating or preventing intestinal diseases, such as inflammatory bowel disease, is developed.